The object of the invention is to provide a fluid cement for medical use having mechanical properties suited to filling spongy bone tissue, as well as a binary composition intended for the preparation of such a cement.
Bone cements have been used for many years to promote the fixation of artificial implants to the skeleton. The cement used as junction between the bone and the implant has to meet a number of requirements. In particular it has to be non toxic and biocompatible. Some cements have even been studied for their bioactive properties, in other words their action promoting adhesion and cell growth on the implant.
Since the mid 1980s, the use of cements has extended to bone repair and first of all percutaneous vertebroplasty. This minimally invasive technique enables a cement to be injected through a trocar into a fractured vertebra to provide bone volume and stabilization. The first percutaneous vertebroplasty was performed in 1984 and has since seen increasing success, opening the way to the plastic repair of other types of bone.
In the United States, between 400,000 and 500,000 clinical osteoporetic vertebral fractures occur every year. Approximately one third of these patients develop a debilitating chronic pain that does not respond to conservative treatment. For many people, this marks the end of an independent way of life. Such patients may be successfully treated through the percutaneous injection of bone cement into the fractured vertebral body. In this technique, a surgical cement paste is carefully injected by percutaneous route, by means of a long canulla, directly into the spongy bone of the fractured vertebral body. The main benefit of this technique lies in the fact that up to 90% of patients feel a relief of pain within 24 hours. (Jensen, M. E. et al. (1997). Am. J. Neuroradiol. 18, 1897-1904).
The cements used until now have been organic polymers, formed from a mixture of a prepolymer, generally PMMA (poly(methyl methacrylate)) and a monomer, generally MMA (methyl methacrylate), reacting in the presence of a polymerization activator.
Most commercially available cements are packaged in the form of two separate components: a powder mainly comprising beads of prepolymer and a liquid mainly containing the monomer. The initiator, for example benzoyl peroxide (BPO), is generally incorporated in the powder, whereas the liquid contains a chemical activator (catalyst) such as dimethyl-para-toluidine (DMPT), the polymerization reaction starting when the two components are mixed together. Further, in order to avoid any spontaneous polymerization that could occur during storage, a stabilizer, usually hydroquinone, is incorporated in the liquid component. The activator and the initiator are introduced in an amount of 0.2 to 2.5% in the corresponding component, the stabilizer for its part being effective at a few tens of ppm.
In order to visualize the cement during and after the operation by radiological means, a radiopaque substance may be added to the powder of prepolymer beads, usually barium sulfate (BaSO4) or zirconium dioxide (ZrO2).
These binary compositions for the preparation of bone cements, originally developed for the fixation of implants and the sealing of prostheses, meet the mechanical criteria of flexural and compressive strength, chemical neutrality and biocompatibility. They are approved for medical use and have proven their long term properties when the skeleton is subjected to considerable and repeated stresses. It is for this reason that bone cements for the fixation of implants have been considered as favored materials for bone reconstructive surgery and, in particular, in vertebroplasty or kyphoplasty.
Although this technique is employed more and more widely, concerns are been raised as regard the associated risks, and particularly fractures of vertebrae adjacent to the cemented vertebral bodies. This is one of the most serious usual complications, entailing a new vertebroplasty procedure. Apart from the volume and the distribution of the injected cement, which play important roles in re-establishing the mechanical properties of the fractured vertebral bodies (Liebschner M. A., et al. (2001) Spine 26, 1547-54), the high stiffness of cements compared to the trabecular vertebral bone is considered as one of the main risk factors in fracturing levels adjacent to the cemented bodies (Zoarski G. H., et al. (2002) J. Vasc. Interv. Radiol. 13, 139-148, Baroud G. et al. (2006) Joint Bone Spine 73, 144-150).
The cementation of a fractured vertebra results in a redistribution of the stress field within the treated vertebra and adjacent vertebral bodies, which is at the origin of subsequent fractures [Fribourg D., et al. (2004) Spine 29, 2270-76, Liebschner M. A., et al. (2001) Spine 26, 1547-54, Baroud G., et al. (2003) Comp. Methods Biomech. Biomed. Eng. 6, 133-39, Polikeit A., et al. (2003) Spine, 28(10), 991-96]. The presence of a cemented vertebra in a functional vertebral unit (two adjacent vertebral bodies and an intervertebral disc) has the effect of significantly reducing its fracture strength by 19% on average, the fracture systematically occurring in a non-cemented vertebral body (Berlemann U., et al. (2002) J. Bone Joint Surg. Br. 84, 748-52).
This result supports other biomechanical studies that have shown that the injection of acrylic cements into an isolated and non-fractured vertebra increases its compressive strength and its compression stiffness (Liebschner M. A., et al. (2001) Spine 26, 1547-54, Belkoff S. M., et al. (1999) Bone 25, 23S-26S, Wilson D. R., et al. (2000) Spine 25, 158-65, Belkoff S. M., et al. (2000) Spine 25, 1061-64, Heini P. F., et al. (2001) Eur. Spine J. 10, 164-71]. Finite element modeling has demonstrated an increase in the compression stiffness of adjacent vertebral bodies ranging between 13 and 18%, and in the hydrostatic pressure within intervertebral discs of about 11% following simulation of a vertebroplasty operation with an acrylic cement (Baroud G., et al. (2003) Comp. Methods Biomech. Biomed. Eng. 6, 133-39, Polikeit A., et al. (2003) Spine, 28(10), 991-96, Baroud G., et al. (2003) Eur. Spine J. 12, 421-26).
An increase in the discal pressure has been evidenced (Ananthakrishnan D., et al. (2003) Annual meeting of the American Academy of Orthopaedic Surgeons, New Orleans, 472) and may be explained by a deformation of the curvature and a reduction in the compliance of the vertebral end plates of the increased vertebrae (Baroud G., et al. (2003) Comp. Methods Biomech. Biomed. Eng. 6, 133-39). A recent biomechanical study concerned with the evolution of the mechanical properties of functional vertebral units constituted of three vertebrae and two discs has shown that the vertebral end plates of cemented vertebrae fracture systematically, unlike the functional control units (Moore S., et al. (2008) Griboi 2008, Montreal, Canada, p 22).
Existing acrylic cements allow mechanical properties that meet the prevailing regulatory requirements. However, these requirements have been established for cements for which the specific indications are the fixation of implants or the sealing of prostheses and for which the criteria in terms of mechanical properties are not suited to vertebroplasty, kyphoplasty or cementoplasty. The elastic modulus and the mechanical strength of cements based on acrylic resins required by the standards are very high compared to the mechanical properties of human spongy bone. This difference in mechanical impedance has been identified as a risk factor increasing the occurrence of fractures of vertebrae adjacent to the cemented vertebral bodies.
The stiffness of a structure may be linked to its modulus of elasticity or Young's modulus, a physical value easily determined by those skilled in the art. Static compression measurements on human vertebral spongy bone have made it possible to determine a Young's modulus between 100 and 800 MPa, the value being dependent on the bone density, the orientation of the trabeculae, the sample preparation, etc., whereas conventional vertebroplasty cements have values between 1,800 and 2,500 MPa. The modulus of elasticity and the mechanical compressive strength of human vertebral spongy bone are respectively 20 and 36 times lower on average compared to the acrylic cements currently injected by vertebroplasty or kyphoplasty (Hou F. J., et al. (1998) J. Biomech. 31, 1009-15, Fyhrie D. P. et al. (2000) Bone 26(2), 169-73, Banse X., et al. (2002) J. Bone & Mineral Res. 17(9), 1621-28, Shim V. P. W., et al. (2005) Int. J. Impact Eng. 32, 525-540).
In order to eliminate this mechanical disparity, the mechanical properties of PMMA cements must be adjusted to those of vertebral spongy bone. The result would then be a better distribution of stresses and thus a notable reduction in the risk of adjacent fractures.
The implementation conditions of cements in percutaneous surgery imply that the injectability criteria of the bone cement must be met on penalty of accidents, the effects of which may be dramatic for the patient such as paraplegia. For this reason, the practitioner needs to have a cement sufficiently fluid for it to be able to flow through a trocar of a few millimeters diameter and for it to retain this fluidity long enough for the practitioner to have the time to operate with full peace of mind.
Furthermore, the injected cement, even in small quantities, must be able to be visualized permanently during the operation by fluoroscopy.
Another serious drawback lies in the fact that the polymerization reaction of acrylic bone cements is exothermic, the temperature being liable to exceed 80° C. at the core of the cement in the vertebral body. Indeed, whereas in arthroplasty the thickness of acrylic cement forming the junction between the bone and the prosthesis does not exceed a few millimeters, enhancing the dissipation of the heat generated by the polymerization reaction, in vertebroplasty it can be more than one centimeter. This configuration has the consequence of limiting the dissipation of the calories generated and thereby contributing to a considerable rise in temperature at the core of the cement. This excessive temperature leads to a necrosis of the neighboring tissues. A temperature not exceeding 50 to 60° C. is preferable for the injection of surgical cements.
Thus, currently known cements, although they are efficient for the stabilization of fractures of osteoporotic vertebral bodies by percutaneous route, do not take into account the biomechanical specificities behind the phenomenon of adjacent fractures.
The prior art has demonstrated the existence of a composition that partially attempts to meet this problem. It involves an injectable mixture comprising a conventional two component powder/liquid bone cement, a third component comprising a hydrophilic liquid, non miscible with the cement, and an organic type X-ray contrast agent preferably in the form of an aqueous solution that can completely replace said third liquid component non miscible with the cement (EP1592463B1).
The non miscible liquid component is adapted to come out at the washout of said mixture, resulting in an interconnected porous bone replacement material. The resulting porosity has the effect of reducing the stiffness of the polymerized mixture to a level comparable to that of spongy bone.
The choice of the authors not to use a hydrophilic inorganic solid contrast agent such as barium sulfate (BaSO4) or zirconium oxide (ZrO2) is explained by the use of a third aqueous liquid component and to obtain an interconnected porosity according to their invention. Indeed, a selective accumulation of these contrast agents in the aqueous phase would result, after washout, in the release of particles of BaSO4 or ZrO2 into the body at a high level of toxicity. This phenomenon is favored by the interconnectivity of the pores, which enables an easy elimination of the particles present within the injectable mixture towards the body via the free circulation of physiological fluids. In terms of biocompatibility, the reduction in the stiffness of the polymerized mixture by the creation of an open and interconnected porosity by means of a third hydrophilic liquid component cannot therefore be conceived in the presence of a powdery solid contrast agent. It is for this reason that it is claimed to use an organic contrast agent in aqueous solution based on iodine and reaching 20% by weight of the injectable mixture. Nevertheless, those skilled in the art can easily recognize that the maximum iodinated contrast agent content disclosed inpatent EP1592463B1 does not make it possible to obtain a contrast as high as through the use of solid contrast agents such as BaSO4 or ZrO2 that may currently be used up to 60% by weight of surgical cements in vertebroplasty or kyphoplasty.
Furthermore, in order that the polymerized cement is always radiopaque after washout of the contrast agent contained in the liquid component non miscible with the cement, it is disclosed that a lipophilic contrast agent miscible in the PMMA phase may be added. The addition of a fourth component to this formulation only makes its preparation more difficult.
Thus, certain requirements linked to the use of an acrylic cement for filling bone tissue in terms of fluoroscopic visualization of the cement during the surgical operation and while monitoring patients, ease of preparation, and effectiveness of the third phase introduced into the cement to promote the creation of a controlled porous structure (control of the size and the dispersion of the pores formed) are not fully resolved by the invention of patent EP1592463B1.
The object of the present invention is a bone cement suitable for use in bone reconstruction surgery, especially for filling a vertebral body, which makes it possible to meet the abovementioned requirements that are not fulfilled by the creation of a composite bone substitution structure composed of a matrix of identical composition to a radiopaque bone cement and with a homogeneous dispersion of zones of lower density and controlled dimensions. This composite structure allows a stiffness equivalent to or slightly greater than that of human vertebral spongy bone.